# Predicting Δ‑9-Tetrahydrocannabinol-Induced Psychoactive and Cognitive Effects: A PBPK–PD Approach to Quantifying Feeling High and Reduced Alertness

## TL;DR

This study creates models to predict how THC affects feeling high and alertness, using brain concentration data from different administration methods.

## Contribution

A verified PBPK–PD model for quantifying THC-induced psychoactive and cognitive effects across various administration routes and doses.

## Key findings

- The models accurately captured dose–response relationships for feeling high with THC doses from 2 to 86 mg.
- An indirect response model effectively described alertness reduction after inhaled THC with doses up to 69.4 mg.

## Abstract

The increasing use of cannabis for medicinal and recreational
purposes
highlights the need to understand its psychoactive effects. Δ-9-tetrahydrocannabinol
(THC), the primary psychoactive cannabinoid, is responsible for feeling
high and reduced alertness after cannabis use. This study aimed to
develop and verify physiologically based pharmacokinetic–pharmacodynamic
(PBPK–PD) models to quantify the effects of THC and its active
metabolite, 11-hydroxy-THC, on feeling high and reduction in alertness
in healthy adults. The models were developed using Simcyp, based on
our previously verified THC PBPK model. A direct response model with
a maximum effect (E
max) function driven
by the brain concentrations and an effect compartment was used to
describe visual analogue scale (VAS) scores for feeling high after
intravenous, oral, and inhaled THC administration. An indirect response
model with an E
max function driven by
the brain concentrations was used to describe the reduction in VAS
alertness scores after inhaled THC. Our models accurately captured
the dose–response relationships for THC doses ranging from
2 to 86 mg for feeling high, and 2 to 69.4 mg for alertness reduction.
The verified PBPK–PD model provides a robust tool for predicting
the psychoactive and cognitive effects of THC, enabling improved assessment
of cannabis-induced responses across diverse populations.